Project Summary/Abstract Our overall strategy for Hesperos is to utilize microphysiological systems in combination with functional readouts to establish platforms capable of analysis of chemicals and drug candidates for toxicity and efficacy during pre-clinical testing. This is a service based company that is developing low-cost in vitro systems containing a novel ?pumpless? microphysiological platform and serum-free medium formulation. The pumpless integrated system, using a rocking motion to pump the cellular medium, reduces the complexity and cost of the fluidic circuit design and simplifies set-up and operation of the device. The system employs microelectrode arrays and cantilever systems that are integrated on chip to allow for noninvasive electronic and mechanical readouts. These functional readouts greatly reduce the number of biomarkers to be monitored for cell health and function in our systems. We have constructed physiological systems that represent human cardiac, skeletal muscle, neuronal, liver, vasculature, blood brain barrier, gastrointestinal tract and neuromuscular junctions (NMJs). Various combinations of these organ modules can be integrated onto a single platform to examine interactions among organs due to interchange of drug metabolites or cell signaling molecules produced in response to drugs. Hesperos has worked with 7 firms using these multi-organ systems for preclinical evaluation of drugs or toxicity tests on chemicals. Hesperos received a Phase II grant from NCATS to apply advanced manufacturing technology to increase throughput and decrease the cost of the device. We have made major advances in our Phase II grant to the point where Dr. Lili Porter (NCATS SBIR Administrator) and Dr. Dan Tagle (Program Manager of NCATS SBIR Program) have approved and encouraged Hesperos to submit a Phase IIB application. To move this technology to a level where it can be cost effective for routine applications in preclinical studies we propose a number of modifications to further reduce manufacturing cost and improve performance and reliability. In an attempt to validate the system, we will partner with AstraZeneca, Roche Pharma Research (a heart/liver/hemodynamic model to test for cardiac safety) and Bioverativ (to validate a Myasthenia Gravis model using an NMJ system). We will determine if these systems can predict semi-qualitative multi-organ responses to those drugs and compare to human clinical data where available. These studies will provide a basis for validation and qualification with the FDA. Aim 1 will make the use of the 4-organ system easier to incorporate into the workflow at pharmaceutical firms and should reduce the cost of use to significantly less than animal studies and provide the advantage of prediction of response in a human system. Aim 2 will utilize Hesperos?s systems to validate these 3 platforms for FDA qualification. While the systems still have significant value to pharmaceutical (or food or cosmetic companies) without FDA approval, FDA approval would greatly accelerate adoption of this technology.